Semiconductor-sensor based near-patient diagnostic system and methods

ABSTRACT

A semiconductor sensor-based near-patient diagnostic system and related methods.

RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.62/381,137, filed Aug. 30, 2016, which is incorporated herein byreference in its entirety.

BACKGROUND

Recent advances in genomics and proteomics now enable use of biomarkersto detect diseases at an early stage, predict optimal therapytailor-made for specific patients and monitor therapy responsiveness.Despite the promise of biomarkers in screening, diagnosis and treatment,very few biomarker-based tests are currently in clinical use. There is alag in the translation of biomarker research into clinically relevanttests, in spite of the potential impact of biomarker testing on costeffectiveness of detection and treatment, and on overall economic burdenof care. Though this problem arises due to technical, financial andregulatory challenges linked to the development and incorporation ofbiomarker testing into clinical practice, the central problem seems tobe the lack of a low-cost platform technology that can be employed atthe point of care within the current clinical workflow.

Specifically in cancer care, there is a need for developing tools thatcan rapidly classify the individual patient's disease according to itsmolecular “fingerprint”, which may include detecting the presence ofhundreds of biomarkers or genes. Such a tool must generally also berelatively inexpensive, in particular for more frequent testing andmonitoring at the point of care or in a near-patient setting.

There is a need for near-patient testing for markers for heart attackand stroke that can be employed at the point of care (e.g., home,ambulance, doctor's office, etc). Such a test must generally be donewith a device that is small and portable, inexpensive and easy to use.In addition to the need for use by untrained professionals, it is alsogenerally important for the device to provide the test results in ashort time frame (for instance, seconds to minutes) so that immediatetreatment can be performed. Fast diagnosis is in particular importantfor disease-related events such as heart attack or stroke that are timecritical. In addition, it is generally important for the test results tobe shared among care provider professionals including doctors, nurses,emergency service providers and specialists. Furthermore, analysis ofthe test results may be performed in situ (within the device) orremotely (using cloud-based computing). Such analytics may aid theclinician in providing the best actionable decision. Therefore, it canalso be important for the device to possess connectivity (via wifi,Bluetooth or other forms of wireless or wired communication systems) toperform a two-way communication (send and receive) for data analyticsand decision-making process.

The current standard in diagnosis and monitoring using biomarkers is acentral-lab based device that is expensive and cannot be used at thepoint of care. This application describes a working prototype, which isa handheld device that enables low-cost testing of the exact sameanalyte at the same clinically relevant level. This device is based onnanosensor technology, using which a wide variety of biomarkers havebeen detected at the required clinical levels for early diagnosis,staging and monitoring of therapy.

Furthermore, it has been possible to miniaturize the prototype into asmartphone plugin, where the plugin or the cartridge contains thesensor, microfluidics and measurement electronics, and the smartphoneacts as a reader. The disposable plugin cartridge is designed to workwith a smartphone to perform multiplexed tests of multiple analytes. Inaddition to the hardware necessary for detection of multiple markers atthe required levels of sensitivity and specificity, the output data isdesigned to comply with necessary analytics (through multivariateregression analysis and other probabilistic distribution methods) forthe proper interpretation and actionable decision by the necessary usersand stakeholders (patient, doctor, caregiver, payer etc).

SUMMARY

A semiconductor sensor-based near-patient diagnostic system and relatedmethods are described herein.

In one aspect, a device is provided. The device comprises a sensormodule including a sensor chip configured to sense chemical orbiological entities and a reader module configured to send control andcommand signals to the sensor module to perform a task. The devicefurther comprises a communication channel configured so that the readermodule and the sensor module have a two-way communication.

In another aspect, a device is provided. The device comprises a sensorincluding at least one sensor element and a sample collection unitconfigured to collect a sample. The sample is applied to the sensor fordetection of the presence of at least one chemical or biological entity.

In another aspect, a device is provided. The device comprises a sensorincluding at least one sensing element and an integrated circuit. Theintegrated circuit is configured to electrically drive the sensor and toprocess at least one electrical signal received from the sensor. Thesignal represents the presence or absence of a selective chemical orbiological entity.

Other aspects will be understood from the following description.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows (Left) Photograph of prototype device (black box) with anexposed multiplexed sensor, with fluidic chamber mated to silicon sensorelement; and (Right) Optical micrograph of device showing fluidicconnections and electrodes, including electron micrograph of sensorarray.

FIG. 2 shows A system flow diagram of the nanowire sensor and themicrofluidic system.

FIG. 3 shows the basic system architecture containing a sensor module, areader module and a method to communicate.

FIG. 4 shows (Left) Device configuration involving a disposable plugincartridge to be used with a smartphone; and (Right) A prototype(designed for biomarker detection with discrete electronics). The frontpart of the PCB (printed circuit board) contains the sensor andmicrofluidics, and the back part contains the measurement and processingcircuit.

FIG. 5 shows a system-level architecture of the proposed multiplexedbiomarker assay system. The (disposable) plugin cartridge will containthe nanosensor chip and the integrated circuit. A smartphone or ahandheld box with smartphone functionalities will interface with thedisposable plugin cartridge for data acquisition, analysis andmanagement.

FIG. 6 shows a treatment pathway involving a single marker

DETAILED DESCRIPTION

A semiconductor sensor-based near-patient diagnostic system and relatedmethods are described herein.

Sensor Architecture

The semiconductor industry has long demonstrated how miniaturization canresult in cost reduction without sacrificing capability. Thisapplication is focused on incorporating semiconductor-processingtechniques to develop nanoscale processor chips and systems forsimultaneous diagnosis and/or prognosis of multiple disease biomarkers,tumor cells and other relevant analytes.

FIG. 1 shows a prototype (black box) with the exposed multiplexedsensors, functionalized and capable of detecting multiple biomarkers atthe same time. The presence of a biomarker is detected by a nanoscalefield-effect transistor sensor through the measurement of conductancechange of bio-functionalized nanowires. These nanoscale sensors serve asfundamental building blocks of our proposed sensor chip. The change inconductance is primarily due to the contribution of surface (charge)states to the conductance, which for larger sensors is dominated byvolume effects. The fractional change is greatest for the smallestsensors, due to the increased surface-to-volume ratio. The presence ofcharged proteins on the surface of an active nanowire induces a largefractional change in the nanowire conductance, and enables relativelyeasy detection.

Nanoscale ion-sensitive FET (field effect transistor), fabricated with a“bottom-up” method, has been shown to be an effective way to monitor theconcentration of homogeneous chemical and biological entities in thesolution by detecting the changes in the surface potential, due toeither point charges or dipoles associated with biomolecules. Incontrast, we adopt a “top-down” method for device fabrication and createa nanoscale biosensor with complete control of the geometry, allowingfor operation under conditions of controlled bias. The geometry andalignment of the nanowire can be fully controlled by lithography andstandard semiconductor processing techniques in a CMOS-compatibleprocess. The silicon nanowires are fabricated from Silicon-On-Insulator(SOI) wafer by electron beam lithography and surface nanomachining,which provide highly controllable nanowire sensors in comparison toother nanoelectronic approaches.

With recent advances in nanotechnology, it is now possible to combinehigh sensitivity at a resolution of sub-ng/ml, with multiplexing. Wepropose to investigate the feasibility of incorporating multiple sensorson a single chip module, laying the foundation for later studies thatmay lead to a high-throughput, sensitive, parallel biosensor chip forcancer markers based on nanotechnology methods.

Since the critical dimensions of the nanowires range between 50-100 nm,these devices can also be manufactured using optical lithography instandard semiconductor foundries.

FIG. 2 shows a system flow diagram. Fluid sample is injected into afluid chamber that contains the nanosensors. PDMS gel is used to sealthe device and surround the nanowire, which is bathed in a fluid volumeof 30 microL, connected to a syringe pump. The size of the cellrepresents a compromise between diffusion and advection, and thelimitation set by the pressure gradient required to drive the solutionpast the nanochannel surface. The measurement circuit includes a smallAC (alternating current) modulation, superimposed on the DC (directcurrent) bias across the nanowire. The AC-modulation voltage and the DCbias voltage are added by a non-inverting summing circuit integratedwith the preamplifier circuit. Differential conductance measurements aretaken by sweeping the DC bias at constant AC modulation amplitude. Thequantity of interest is delta G, the change in the differentialconductance due either to a change in the reference gate voltage deltaV_(g), or to a change in molecular concentration delta m.

A potential applied to the top gate V_(t) sets up an electric field thatmodulates the conductance channel between source and drain, and can beused to amplify small signals. If the top gate is replaced withfunctionalized surface binding sites, the binding of charged moleculeswill change the surface potential in addition to reference gate voltageV_(rg). This surface potential change can modulate the conductancebetween source and drain. There is an equivalence between theconductance modulation produced by a change in the analyteconcentration, and that produced by a change in the top gate voltage.

Small changes in the conductance of the device can be measured byconsidering the differential conductance with the derivative taken atconstant V_(t). This method yields measurements at highersignal-to-noise ratio compared to digital method of taking derivatives.The differential conductance G depends on top gate voltage V_(t) oranalyte concentration m in solution as well as bias voltage V_(ds). Asmentioned above, measurement is needed of the change in conductancedelta G, due either to a change in the top gate voltage V_(t), or due tochange in concentration delta m. Higher signal delta G can be obtainedin the region of negative V_(ds) or positive V_(t) for our nanosensor.

Device Architecture

The basic structure of the device contains the following elements:

-   -   1) A sensor module comprising of the sensor chip, capable of        sensing analytes (markers and/or biological entities);    -   2) A reader module capable of sending control and command to the        reader to perform the necessary task, sending additional        information such as calibration data for on-chip data        processing, reading out the sensor data and sharing data;    -   3) A communication channel, either wired or wireless, so that        the reader and the sensor can have a two-way communication.

In addition to the basic configuration, shown in FIG. 3, the readermodule may also contain necessary electronics to share or receive dataand command/control sequence with another system capable of performinganalytics. This system could be a cloud computer or a network that maycommunicate with the reader through either wired or wirelesscommunication. The analytics performed by this system may provide anactionable decision or support data and analysis for a clinician orhealthcare professional to make that decision.

Depending on application, the device configuration will build on thiselementary system architecture. In order to elucidate thisapplication-specific device configuration, it is important to understandthe range of device applications, as listed in Table 1 below.

Implantable Device

In one embodiment, the device could be implantable, where the device isembedded inside the body for diagnosis or monitoring. For instance, itcould be a continuous glucose monitoring device that detects glucose inblood, tear or interstitial fluid. What is implanted is the sensormodule depicted in FIG. 3. The reader module could be a handheld ortable-top device capable of communicating with the implanted module,typically wirelessly. In addition, the reader module may be used forwireless charging of the implanted sensor module for long-termoperation. The reader module could be a modified smartphone or braceletthat can be worn by the patient. Furthermore, an implanted module couldalso contain a drug delivery system for remote release of theappropriate drug into the body. For instance, an implantable glucosemonitoring device could contain an insulin delivery module that canrelease insulin into the bloodstream depending on the blood sugar level.In a different configuration, a glucose sensor can be implanted in theeye for detecting glucose level in the tear.

TABLE 1 Device Categories Implantable device Subcutaneous device E-patchE-tattoo Wearable (ring, bracelet, watch) Smartphone plugin Handhelddevice Tabletop box Central lab equipment

Subcutaneous Device

In another configuration as a subcutaneous device, the sensor module canbe located on the skin or under the skin. In certain applications, thedevice can be embedded under the skin or applied as a patch. The sensormodule can access a range of analytes in this configuration. Theseanalytes can be detected in blood vessels and nerves in the dermis.There are also different types of cells found in the hypodermis, whichinclude adipose cells, fibroblasts and macrophages. In addition to thesecells, the body also secretes an oily, waxy matter called sebum throughwhat are known as the sebaceous glands. The sebum mostly containstriglyceride, squalene, wax esters and metabolites of usually fatproducing cells. In addition, secretion rate of sebum can be used tomonitor some hormones such as testosterone, estrogen, and progesterone.The sensor module can be configured to detect these elements in thesebum, which can be used as markers for diagnosis or monitoring ofspecific diseases. Sensing of analytes in the sebum can also be used fordiagnosis of infectious diseases (bacterial or viral infection) andinflammation. Similar to the glucose-insulin integrated system discussedabove, a subcutaneous device can be used to both detect analytes anddeliver drugs that may include hormones, antioxidants, anti-inflammatoryand antimicrobial lipids. Other variations of a subcutaneous devicecould be an electronic patch (e-patch) or an electronic tattoo(e-tattoo), located on the skin or under the skin.

Wearable Device

In yet another configuration, the sensor module and the reader modulecan be combined as a single wearable device. Examples of this includearm and leg bracelets, earrings and other wearable configurations on thebody. In one variation, the device can be worn as a wrist watch, whichcontains the sensor and the reader with connectivity. Fluid sample fromthe body such as a drop of blood can be applied to an exposed surface ofthe device, which will sense the desired analyte in the fluid sample. Inanother variation, it is possible to connect a disposable cartridge,which can be plugged into the device. The cartridge will contain theappropriate fluid sample to be tested.

Smartphone Plugin

In another configuration, the sensor module can be a plugin cartridgefor a smartphone or a smartphone configured as a reader with essentialfunctionalities such as connectivity and basic data processingcapabilities with an app. The plugin cartridge can be connected directlyinto a smartphone or smartphone-like reader, or the cartridge can belinked with the reader by near field communication (NFC) such asBluetooth. Typically, the user interface or an app can be used to enablemeasurement and presentation of the marker levels in the fluid sample.In addition, connectivity (cellular, WiFi, Bluetooth, GPS etc) is usedto share, store and/or analyze data with a system at a remote location.

Handheld Device

In the handheld device configuration, the reader module is similar tothe smartphone-like reader described above. It can use either adisposable plugin cartridge or it can be an integrated system containingthe sensor module inside, so a fluid or other samples can be presentedto the device for testing. Because of the superior multiplexingcapabilities of the semiconductor sensors, it is possible to detectmultiple test panels simultaneously.

Table-Top Device and Central Lab Equipment

In this standard configuration, it is possible to considerably increasethe system functionality by having test menus that can be adapted to anyapplication. Most disease types can be covered by a panel of 100-150analytes with a single test, and test types can include protein markers,genetic markers, circulating cells and other entities such as bacteriaand virus. In addition to testing for certain diseases, suchall-inclusive tests can also be used for wellness checks, where acomprehensive (male or female) wellness panel can further includestandard panels such as complete blood count (CBC) or metabolic panel.

System-Level Architecture

The complete system comprises of the two modules, sensor module andreader module, discussed above. In addition, it includes remote oron-board analytics for data analysis, processing and bioinformatics,necessary to arrive at actionable decision for the care provider. FIG. 5elucidates an example where a smartphone plus plugin cartridge systemconnects wirelessly to a remote analytics/database system for furtherdata processing. For example, a test panel including a number ofbiomarkers may require multivariate regression analysis to provide thenecessary analytics for actionable decision. The analysis may includepatient's personalized data to create a profile for each test to aid theclinician with their decision making process.

Table 2 lists examples of two panels, one for heart attack and the otherfor stroke. These panels include multiple tests that must be performedquickly in certain situations for actionable decision towards patientcare. In addition to such time-sensitive tests, there are tests, resultsof which might necessitate further tests.

TABLE 2 Cardiac panel Cardiac - Troponin, BNP, Glucose, Electrolytes,BUN/Creatnine, Heart Attack CBC, Lipids Cardiac - BNP, pro-BNP,BUN/Creatnine, K+, Na+, Glucose, Hgb/Hct, Heart Failure WBC, Platelets

Treatment Pathway—Test Panel Algorithm

Most markers can be used for screening, diagnosis, staging, prognosis ormonitoring for therapy responsiveness, and monitoring for remission.Different stages in this care continuum usually correspond to differentlevels (or concentrations) of the biomarker(s). FIG. 6 shows a treatmentpathway involving a single marker. Similar pathways can be developed fortest panels that contain tests of multiple markers. Certain markerlevels may need to be monitored much more frequently, which necessitatesfor those tests to be done at the patient's home, without requiring thepatient to make frequent hospital visits. The system architecturedescribed earlier enables home testing, where the data can be remotelyshared with the clinicians and care providers, almost instantly.

1. A device comprising: a sensor module including a sensor chipconfigured to sense chemical or biological entities; a reader moduleconfigured to send control and command signals to the sensor module toperform a task; a communication channel configured so that the readermodule and the sensor module have a two-way communication.
 2. A deviceas described in claim 1, where the sensor chip is a silicon sensor.
 3. Adevice as described in claim 1, where the sensor chip comprises one ormany silicon sensors.
 4. A device as described in claim 1, where thesensor element comprises at least one nanowire.
 5. A device as describedin claim 1, where the sensor element operates as a field effecttransistor.
 6. A device as described in claim 1, where the sensor chipcomprises at least one sensing element and at least one integratedcircuit.
 7. A device as described in claim 1, where the sensing elementhas at least one critical dimension less than one micron in size.
 8. Adevice as described in claim 1, where the reader module is selected fromthe group consisting of a phone, a tablet, a watch, a wearable and astandalone box.
 9. (canceled)
 10. A device as described in claim 1,where the reader is configured to communicate with a server for furtherdissemination of the information.
 11. A device as described in claim 1,where the reader is configured to wirelessly communicating with a cloudserver for storing, analyzing and disseminating the data.
 12. A deviceas described in claim 1, wherein the communication channel is configuredto be wired or wireless.
 13. A device comprising: a sensor including atleast one sensor element; a sample collection unit configured to collecta sample; where the sample is applied to the sensor for detection of thepresence of at least one chemical or biological entity.
 14. A device asdescribed in claim 13, where the sample is selected from the groupconsisting of blood, sweat, saliva, urine and other physiologicalfluids.
 15. A device as described in claim 13, where the collectedsample is allowed to enter and/or leave the sensor element contained ina microfluidic chamber.
 16. A device as described in claim 13, where thecollected sample is allowed to flow through a tube, containing acoagulant or an anticoagulant.
 17. A device as described in claim 13,where the collected sample is passed through a filter.
 18. A device asdescribed in claim 13, where the filter is used to remove or separatered blood cells.
 19. A device as described in claim 13, where the filteris used to remove or separate the salt content in the sample.
 20. Adevice as described in claim 13, where the filter is used to remove orseparate specific biological materials in the sample.
 21. A devicecomprising: a sensor including at least one sensing element; anintegrated circuit; where the integrated circuit is configured toelectrically drive the sensor and to process at least one electricalsignal received from the sensor; where the signal represents thepresence or absence of a selective chemical or biological entity. 22-28.(canceled)